Discovery of Key Mechanism of Zika Virus Infection Ups Chances of Its Treatment and Prevention

Zika virus infection is transmitted through
the bite of infected mosquitoes and currently has no vaccine or cure.

Zika virus infection during pregnancy is
associated with birth defects and some persons develop Guillain-Barre
syndrome, a rare condition affecting the brain.

Mechanism by which neutralizing
antibody disrupts critical step in the infection process
has been identified.

The discovery could lead to development of drugs
and preventive vaccines

Structure of the Zika virus to which
neutralizing antibody was bound have been analyzed by scientists to reveal the
mechanism of the infection and how the antibody prevents it. The work was
conducted by a team from Purdue University, Vanderbilt University Medical
Center and the Washington University School of Medicine.

Reason for Study

The research team which
undertook the current study had isolated the antibody in an earlier research
published early this year. The antibody was isolated from the blood of a person
who had recovered from Zika infection. They found that the antibody was capable
of neutralizing American, African and Asian strains of the virus and in
addition decreased fetal infection and death in mice.

Discovery of Key Mechanism of Zika Virus Infection Ups Chances of Its Treatment and Prevention

What eluded them then was how the
antibody neutralized the virus, and the current research was
embarked upon to find that answer.

‘Neutralizing antibody binding to Zika virus prevents exposure of fusion peptides that aid in transfer of viral RNA into a host cell, a critical step in the infection process.’

"However, until now what remained
unknown was the mechanism of neutralization of Zika infection by the antibody and the
structural basis for neutralization," said Michael Rossmann, Purdue's Hanley Distinguished Professor
of Biological Sciences.

Methods of the Study

The research team determined the
three-dimensional structure of the Zika virus while attached to a key binding
site on the antibody known as the antigen binding fragment, or a Fab molecule.
They were also able to find how the
virus infects the host cell and the manner in which the neutralizing antibody
prevents this critical step,

The structure was determined by a
technique called cryo-electron microscopy at a resolution of 6.2 Angstroms. The
following were the observations

The genome of the Zika virus is situated within a protective
shell that is composed of 60 repeating units, each
unit containing three envelope proteins, or E proteins.

When the virus attaches to the host
cell's outer membrane a difference in pH, or acidity, in the membrane
causes the envelope proteins to expose "fusion peptides,"
resulting in the transfer of the viral RNA genome, a critical step in the
infection process.

The binding of the neutralizing
antibody to Zika inhibits this important pH-triggering mechanism, thereby
neutralizing the virus by "cross-linking" the E proteins, and
closing them up and preventing the exposure of fusion peptides.

"This hypothesis is supported by
pre- and post-neutralization assays of Zika infection, showing the antibody is
able to significantly inhibit infection," Rossmann said. "This
approach should provide broad-range protection against virtually all strains of
Zika."

Moreover, considering that the surface of
Zika is made of 60 copies of three E proteins, it would be expected that 180
copies of the antibody's Fab molecules would be needed for neutralization.

"However, one antibody binds for six
E proteins, so only 30 are needed," Hasan said. "Therefore, you don't
need a high concentration of antibodies to achieve neutralization."

Zika Virus Infection

Zika virus belongs to the Flavivirus
family which includes dengue, West Nile, yellow fever, Japanese encephalitis and tick-borne
encephalitic viruses.

The first large epidemic of the Zika
virus was reported in 2007 in Micronesia and then in 2013-14 in Oceania. The
most recent outbreak began in Brazil in 2014-15, and has spread to other
countries in South America, North America and the Caribbean. In December 2016
alone four cases of fetal deformities have been reported from New York city.

Zika virus infection is transmitted through
the bite of infected mosquitoes and recent research has established that
maternal to fetus transmission and sexual
transmission is also possible.

"Given the severity of the symptoms
caused by Zika infection in humans, it is crucial to understand the immune response elicited
by the infection to develop neutralizing anti-Zika therapies," Rossmann said.

Scope of the Study

The findings of the study could be
used for the development of antiviral medications

Future research can focus on other
sites on the viral surface where antibodies can attach, which would be of
use in the development of vaccines.

Nipah Virus (NiV) or Hendra virus is a deadly virus that spreads via contact with the saliva, urine, or excreta of fruit bats or pigs. Nipah outbreak is an emerging zoonosis which had resulted in fatal deaths in Kerala, India.

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